Highly diastereoselective boron and titanium mediated aldol reactions of a mannitol derived 2,3-butanediacetal ethyl ketone

Abstract

A mannitol derived 2,3-butanediacetal ethyl ketone displays high levels of diastereoselectivity in boron and titanium mediated aldol reactions with a range of aliphatic and aromatic aldehydes to afford syn aldol products in high yield. The stereochemical outcome of the reaction was determined using J-value analysis, NMR analysis of O-acetylmandelate derivatives and X-ray crystallography.

Introduction

Since its discovery by Borodin [1], and independently by Wurtz [2], the aldol addition reaction has become one of the most important transformations in organic synthesis [3]. Its ability to furnish β-hydroxy carbonyl compounds with excellent levels of stereocontrol has led to its widespread employment in the total synthesis of natural products, particularly secondary metabolites derived from the polyketide biosynthetic pathway [4].

As part of our research exploring the synthetic utility of 2,3-butane-diacetal derivatives of polyol precursors [5], we have previously shown that a simple synthetic sequence can be used to convert D-mannitol (1), via the selectively functionalised intermediate 2 to either the equatorial (3) or axial (5) diastereoisomer of (5R, 6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde at will (Scheme 1) [6].

In many of the reactions in which they act as electrophiles, these aldehydes display excellent stereodirecting abilities, giving rise to a highly versatile stereochemical manifold [7]. Building on this, we wished to explore the use of the 2,3-butane diacetal motif as the stereodirecting group in a nucleophilic reaction partner and chose the aldol reaction as our initial subject of investigation. To this end, the equatorial ethyl ketone 4 was synthesised in high yield from 3 using a simple Grignard-addition/Swern-oxidation sequence. In this manuscript, we report that boron and titanium mediated aldol reactions of 4 proceed with excellent levels of diastereoselectivity, furnishing syn, syn products with a range of aldehydes.

We began our investigation with benzaldehyde, 6a, as the electrophilic reaction partner. Initially exploring the generation of dialkyl boron enolates, a brief survey of reagents and conditions identified dicyclohexylboron chloride and triethylamine in diethyl ether at −60 °C as suitable, giving rise to high levels of stereocontrol whilst allowing the reaction to proceed at an acceptable rate.

Under these conditions, using recently prepared dicyclohexyl boron chloride [8], the coupling of 4 with benzaldehyde afforded a 98% yield of the product 7a in a diastereomeric ratio of 96:4 as determined from ¹H NMR spectroscopy (Scheme 2, Table 1). Using the same conditions, 4 was then coupled with a series of aromatic and aliphatic aldehydes to afford the corresponding aldol products 7a-j in excellent yields and with very high levels of stereocontrol (Scheme 2, Table 1). An oxidative workup with alkaline hydrogen peroxide was used to convert the cyclohexyl groups on boron to cyclohexanol prior to chromatographic purification.

The relatively low α-β ¹H-¹H coupling constants (Table 1, 4th column) are consistent with the newly created stereocentres having a relative syn relationship, according to the Stiles–House model [9]. Although dicyclohexylboron chloride often leads to the formation of E-boron enolates, the enolate geometry is highly dependent on the substitution pattern at the α′ position and related α′-alkoxy ketones have been shown to afford exclusive formation of Z-boron enolates using this reagent [10].

The absolute configuration of the β hydroxyl stereocentre in the aldol products was determined by comparison of the ¹H NMR spectra of their (R)- and (S)-O-acetylmandelate esters [11] (Scheme 3, example Δ(S-R) data are shown for compound 8d).

The stereochemical outcome of the reaction can be explained on the basis of a preferred enolate conformation in which the enolate CO bond and the α′ CO bond are aligned in an antiperiplanar orientation for dipolar reasons. The approach of the aldehyde towards the least hindered face of the enolate in a Zimmerman–Traxler transition state then leads to the observed diastereoselectivity (Scheme 4) [3](k), [12].

p-Bromobenzaldehyde 6b was specifically chosen in the hope that the p-bromobenzene ring might impart crystallinity to the corresponding product 7b. Pleasingly, this turned out to be the case and an X-ray crystal structure was obtained (Fig. 1). In addition to providing further evidence for the relative syn-aldol stereochemistry, the presence of the heavy bromine atom also allowed the absolute stereochemistry to be determined from the X-ray data (which was in full agreement with the O-acetylmandelate analysis).

In addition to the use of dicyclohexylboron chloride, we also briefly explored titanium reagents and found titanium tetrachloride to be equally competent in effecting these transformations (affording the same diastereomer of product) using diisopropylethylamine as the base and dichloromethane as the solvent (Table 1, entries 2,4,6). Conveniently, commercial grade material (purchased as a 1 M solution in dichloromethane) was found to be adequate, providing a possible advantage over the use of dicyclohexylboron chloride. As the titanium derived by-products are all easily hydrolysed and extracted into the aqueous phase on workup, this is also a potential advantage over the boron reagent (which leads to cyclohexyl byproducts whose removal generally necessitates additional workup steps). As the observed stereochemical outcome of the titanium mediated reaction was the same as the boron mediated aldol addition, it is also possible that the transition-state is similar to that shown in Scheme 4. Unlike the boron atom in dialkylboron enolates, the titanium metal in the enolate can bind to additional Lewis basic groups, such as the α′-alkoxy group in 4. This might be expected to lead to the alternative syn aldol stereochemistry via an alternative enolate conformation. However, it is possible that the 2,3-butane-diacetal moiety (containing two adjacent quaternary carbons) would cause too much steric crowding to permit such a chelated structure (Fig. 2). This might perhaps lead to a similar 'dipole aligned' Zimmerman-Traxler transition state as suggested for the boron mediated reaction.

Having established the efficacy of the aldol coupling, we wanted to establish that the 2,3-butane-diacetal group could be removed in order to reveal the keto-diol functionality. Perhaps unsurprisingly, when this was attempted using trifluoroacetic acid (a reagent we have commonly used for this transformation), the reaction was also accompanied by a rapid retro-aldol cleavage (Scheme 5). We also found that the retro-aldol cleavage of 7a was rapid at room temperature using methanolic potassium carbonate, leading to the aldehyde and ketone in quantitative yield (Scheme 5). As yet, we have been unable to determine the order in which the butane-diacetal cleavage and retro-aldol processes occur under acidic conditions.

To prevent the possibility of the retro-aldol process, we acylated the secondary alcohol in 7a. With this change, the butane-diacetal cleavage of the ester 10 was able to be performed in high yield (Scheme 6). We found that a THF-water solvent mixture, which provided a homogeneous reaction mixture after addition of TFA, led to the highest yield (95%) for this reaction.

The keto-triol moiety in 11 could be cleaved to the carboxylic acid 12 in 93% yield using sodium periodate in MeCN-H₂O-DCM. Saponification of the acetate group then afforded the well known hydroxy acid 13. Spectroscopic data and optical rotation values for this compound matched those provided in the literature [13], further confirming the diastereoselectivity of the aldol addition.